孕中期血清学筛查标志物水平与产科不良结局的相关性研究

Association between adverse obstetric outcomes and abnormal maternal serum markers in the second trimester screening

目的·评估孕中期血清学筛查指标甲胎蛋白(AFP)、人绒毛膜促性腺激素(hCG)和游离雌三醇(uE3)异常值与21三体(T21)、18三体(T18)、开放性神经管缺陷(ONTD)之外产科不良结局的相关性,为血清学产前筛查临床应用提供更精准的本地化循证依据。方法·采用回顾性队列研究方法,通过上海交通大学医学院附属国际和平妇幼保健院电子病历系统,随访2012—2014年行孕中期血清学筛查孕妇的妊娠结局,以标志物MOM值水平的第1(P_1)和第99百分数(P_(99))确定极低和极高异常阈值,统计标志物异常与正常组中不良妊娠结局的发生率,获得标志物异常与不良妊娠结局的相对风险,进行组间比较。结果·(1)共25 616例孕妇纳入研究,随访到T21、T18、ONTD之外其他不良妊娠结局4 526例,其中单项不良结局4 143例,合并2项及以上不良结局383例。(2)在标志物异常各组中,AFP和h CG降低与各种不良妊娠结局都无明显相关性,但AFP、hCG升高或uE3降低与多种不良结局相关,其中其他染色体异常相关性最为密切;18例其他染色体异常孕妇中有9例出现以上标志物异常,与对照组相比,各组相对风险分别为13.33、35.00和59.00倍。(3)AFP、hCG升高,uE3降低与<28周的胎儿丢失、出生体质量<同胎龄新生儿体质量的P3及<34周的子痫前期等亚型相关性更为密切,分型后各组相对风险是未分型前的1.5~15倍。结论·临床工作要重视AFP升高、hCG升高、uE3降低的孕妇;建议加强后续产检及B超监测,及早发现各类不良妊娠结局,尤其是早中孕期胎儿丢失、低于P_3的小于胎龄儿、早发型子痫前期等表型严重的部分亚型。

Objective · To evaluate the association between the abnormal maternal serum markers of alpha fetoprotein （AFP）, human chorionic gonadotrophin （hCG） and unconjugated estriol （uE3） in the second trimester screening and the adverse obstetric outcomes other than trisomy 21 （T21）, trisomy 18 （T18） and open neural tube defects （ONTD）, and to provide local data for supporting evidence based clinical managements. Methods · A retrospective cohort study was performed in the women who received second trimester maternal serum screening in the International Peace Maternal and Child Health Hospital between 2012 and 2014, with naturally conceived singleton pregnancies. Obstetric outcomes were followed up by searching electronic medical records within the hospital. Abnormal level of marker was defined as a MOM value ≥ 99th （P99） or ≤？1st percentile （P1） of the overall screened population. Incidence of an adverse obstetric outcome was compared between the groups with abnormal markers and the control with all markers in normal. Results · ① A total of 25 616 pregnancies were included in this study, in which 4 526 were identified as having various adverse obstetric outcomes. Among them 4 143 pregnancies were with isolated and 383 pregnancies were with co-occurring two or more adverse outcomes. ② When compared to pregnancies with normal levels of all three serum markers, pregnancies with decreased AFP or decreased hCG did not show associations with any adverse obstetric outcomes. However, pregnancies with increased AFP, increased hCG or decreased uE3 were at increased risk for a variety of abnormal pregnancy outcome. In 18 pregnancies with an outcome of fetal chromosomal abnormalities other than T21 and T18, 9 presented with either increased AFP, increased hCG or decreased uE3, with relative risk ratios of 13.33、35.00 and 59.00, respectively. ③ The performance of those markers tended to be improved in a subset of adverse obstetric outcomes, including low birth weight 〈P3, fetal loss prior to 28 weeks, and preeclampsia onset before 34 weeks. Compared to the conditions with a broad definition, relative risk ratios increased 1.5-15 folders in these narrowly defined more severe forms. Conclusion · Pregnancies with abnormal serum markers should receive close attention. For women in particular with increased AFP, increased hCG or decreased uE3, invasive prenatal diagnosis for a comprehensive examination of fetal chromosomal abnormalities is strongly suggested. Even in the absence of positive diagnostic result, managements of increased frequency of antenatal visits and ultrasound surveillance should still be offered, in order to achieve an earlier or improved detection of adverse obstetric outcomes, especially of those with severe clinical manifestations such as early fetal loss, small for gestational age infant, and early onset preeclampsia.